Simcyp Simulator: Not just for small molecules

Biological medicines (“biologics” or “large molecule drugs”) now account for 30% of new drug approvals and up to 50% of the pharmaceutical industry’s pipeline. Biologics differ from small molecules because they are much larger, have slower absorption rates, confined distribution, and different elimination. They are designed for a specific target, typically found on the cell membrane, which they bind to with high affinity. Due to this high affinity, the binding to the target and subsequent turnover of the drug–target complex can contribute significantly to the disposition of biologics. The pharmacokinetic (PK) properties of biologics are quite distinct from that of small molecules, as are the interactions with targets (pharmacodynamics).

The Simcyp PBPK Simulator, which has been well established for informing a range of development decisions for small molecules, has been expanded, enhanced, tested and applied to biologics drugs. Simcyp Biologics enables scientists to model many different biologics modalities, including monoclonal antibodies, protein conjugates, Fc-fusion proteins, bispecifics, and other proteins and peptides.

Addressing Key Biologics Drug Development Challenges

Characterizing biologic drugs’ PK in a more mechanistic manner, using Simcyp Biologics will help bring safer, more efficacious treatments to market.

Simcyp Biologics is used to answer many pivotal scientific questions:

  • FIH PK prediction, dose selection and optimization
  • Extrapolation to special populations, such as pediatric and renal impairment
  • Target selection/validation by linking PK to pharmacology
  • The impact of half-life extension approaches on PK and PD eg FcRn mutation, conjugation
  • Disposition and DDI for protein-small molecule conjugates (ADC), combined with small molecule simulator
  • DDIs resulting from cytokine modulation, combined with small molecule simulator
  • Tumor penetration of proteins
  • Target shedding and the impact on target tissue and tumor receptor occupancy
  • The disposition of bi-specific binding proteins
  • Receptor occupancy in specific tissues and linking to PD models
  • Linked to QSP models to investigate immunogenicity
Read paper on Simcyp PBPK and subcutaneous absorption of therapeutic proteins
Combination with Small Molecules – ADCs and beyond

Antibody–drug conjugate (ADC) are antibodies connected to cell-killing, small-molecule payloads via chemical linkers. ADCs combine the target specificity of immunotherapy with the potent anticancer activity of small-molecule chemotherapy. The complex structure of ADCs poses unique challenges to PK and PD characterization because it requires a quantitative understanding of multiple different molecular species (eg, conjugate, total antibody, and unconjugated payload) in different tissues.


The Simcyp Simulator connects its small and large molecule capabilities to support companies in developing ADCs, including several recently FDA-approved drugs. Example modeling projects include,

  • A minimal PBPK for ADC species
  • Connecting released payloads to full PBPK and the rest of the capabilities in the Simcyp Simulator
  • Drug-drug interaction liability from dosing ADC
  • Deconjugation of ADC species in vivo
  • Mechanistic modeling for ADC(or Ab) penetration into tumor
  • Target binding in both normal and tumor tissues (TMDD)
  • A permeability-limited tumor model for released payloads with uptake and efflux transporters
  • Delayed release of payloads
Download Certara blog on ADCs

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